In October 1494, Ludovico Sforza, who had long controlled the Duchy of Milan, finally procured the ducal title after providing a hitherto unheard-of dowry to his niece, who was marrying the Holy Roman Emperor, Maximilian. He was immediately challenged by Alfonso II, who also had a claim on Milan. Ludovico decided to remove this threat by inciting Charles to take up Innocent's offer. Charles was also being encouraged by his favorite, Étienne de Vesc, as well as by Cardinal Giuliano della Rovere, the future Pope Julius II, who hoped to settle a score with the incumbent Pope, Alexander VI.

Charles VIII gathered a large army of 25,000 men, including 8,000 Swiss mercenaries and the first siege train to include artillery, and invaded the Italian peninsula.[1] He was aided by Louis d'Orleans' victory over Neapolitan forces at the Battle of Rapallo which allowed Charles to march his army through the Republic of Genoa.[4] On 19 October, a contingent of Charles' army besieged the fortress of Mordano. After refusing to surrender, the fortress was bombarded, taken by French-Milanese forces, and the surviving inhabitants massacred.[5]

The arrival of Charles's army outside Florence in mid-November 1494[6] created fears of rape and pillage. The Florentines were led to exile Piero de' Medici and to establish a republican government. Bernardo Rucellai and other members of the Florentine oligarchy then acted as ambassadors to negotiate a peaceful accord with Charles.

The French finally reached the city of Naples in February 1495, capturing it without a siege or a pitched battle. Charles stayed in Naples for a number of weeks, but on 20 May 1495, with the newly formed anti-French League of Venice threatening to cut off his return through northern Italy, Charles left Naples to return to France.[7] Charles left Gilbert, Count of Montpensier, in Naples as his viceroy, with a substantial garrison of armed men.[8]

The Italian states, however, quickly realized the danger of foreign monarchy to the autonomy of each of them, and in March 1495 they had agreed to create an alliance known as the League of Venice. After Ferdinand of Aragon had recovered Naples, with the help of his Spanish relatives with whom he had sought asylum in Sicily, the army of the League followed Charles's retreat northwards through Rome, which had been abandoned to the French by Pope Alexander VI on 27 May 1495.[9]

The speed of the French advance, together with the brutality of their sack of Mordano, left the other states of Italy in shock. Ludovico Sforza, realizing that Charles had a claim to Milan as well as Naples, and would probably not be satisfied by the annexation of Naples alone, turned to Pope Alexander VI, who was embroiled in a power game of his own with France and various Italian states over his attempts to secure secular fiefdoms for his children. The Pope formed an alliance of several opponents of French hegemony in Italy: himself; Ferdinand of Aragon, who was also King of Sicily; the EmperorMaximilian I; Ludovico in Milan; and the Republic of Venice. (Venice's ostensible purpose in joining the League was to oppose the Ottoman Empire, while its actual objective was French expulsion from Italy.) This alliance was known as the Holy League of 1495, or as the League of Venice, and was proclaimed on 31 March 1495.[10]England joined the League of Venice in 1496. The League was the first of its kind; there was no medieval precedent for such divergent European states uniting against a common enemy, although many such alliances would be forged in the future.[11]

The League gathered an army under the condottieroFrancesco II Gonzaga, Marquess of Mantua. Including most of the city-states of northern Italy, the League of Venice threatened to shut off King Charles's land route by which to return to France. Charles VIII, not wanting to be trapped in Naples, marched north to Lombardy on 20 May 1495.[7] There he met the League in the Battle of Fornovo, 6 July 1495.[12] When the battle was over both sides claimed victory.[13] Yet, despite their numerical superiority in the battle, the League army took twice as many casualties as the French.[14] However, Charles did successfully march his army across the territories of his enemies on his way to France and the army of the League could not stop him, but he lost nearly all of the spoils from his campaign in Italy.[14] Thus, the battle of Fornovo was a French pyrrhic victory.[15] Charles VIII died in April 1498, before he could regroup his forces and return to Italy.[16]

During this war an outbreak of syphilis occurred among the French troops. This outbreak was the first widely documented outbreak of the disease in human history, and eventually led to the Columbian theory of the origin of syphilis.[17]